Oral Presentation Annual Meetings of the Endocrine Society of Australia and Society for Reproductive Biology and Australia and New Zealand Bone and Mineral Society 2016

An increased risk of miscarriage is associated with dysregulation of granulosal receptor density and lower apoptosis levels (#206)

Sheena LP Regan 1 2 , Phil G Knight 3 , James D Stanger 2 , John L Yovich 2 , Yee Leung 4 , Frank Arfuso 1 , Ghanim Almahbobi 5 , Arun Dharmarajan 1
  1. Stem Cell and Cancer Biology Laboratory, School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, WA, Australia
  2. Pivet Medical Centre, Perth, WA, Australia
  3. School of Biological Sciences, Hopkins Building, University of Reading, Whiteknights, Reading RG6 6UB , UK
  4. Western Australian Gynaecologic Cancer Service , King Edward Memorial Hospital for Women, Perth, Western Australia
  5. School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth , WA, Australia

Ovarian reserve and patient age are implicated in the dysregulation of receptor signalling during follicular development that potentially reduces fertility, oocyte quality and pregnancy success.

The in vivo granulosa receptor density was measured by flow cytometry. Immunolabelled granulosa cells were collected from 401 individual antral follicles, from 57 IVF patients (23-45y). The receptor protein density for LHR, FSHR and bone morphogenetic receptor (BMPR1B) was quantified by the average fluorescent intensity of ~8000 granulosa cells/individual follicle, from follicles 4-26 mm in diameter. Patient tracking of the fate of each oocyte to pregnancy was performed. The unique data shows the receptor density in relation to the fertilisation and embryo transfer success rate, to produce a pregnancy. The receptor density of the follicle that resulted in miscarriage was compared to the continuing pregnancy level.

The density of the LHR protein was expressed at a constant level on the granulosa cell surface from 8-19 mm in the young patient whereas, the largest follicles (24mm) expressed significantly less FSHR, BMPR1B and LHR, indicating a pre-requisite down-regulation during luteinisation. The LHR density and apoptosis was significantly reduced (p<0.01) in the follicles that resulted in miscarriage compared to a continuing pregnancy.

This shift in correlation between BMPR1B, FSHR and LHR with ovarian ageing suggests that the dysregulation mechanism involved is associated with the overall lower levels of receptor density and the lack of receptor down-regulation, essential to maturation of the granulosa cells.

The dysregulation may impede luteinisation, and have a negative clinical impact on the progesterone surge, resumption of meiosis and germinal vesicle breakdown (Regan, et al. 2016, MCE: Regan, et al. 2015, Reproduction). Future assisted reproduction treatments may target restoring the optimum receptor density profile to improve oocyte quality and reduce the miscarriage rate.